Promising new gene therapy for HIV immunity

Penn's Carl June, an expert in gene therapy, developed a new tool.
Penn's Carl June, an expert in gene therapy, developed a new tool. (University of Pennsylvania)
Posted: March 03, 2011

In a feat that is renewing hopes for conquering AIDS, researchers have genetically engineered patients' vital immune cells to make them resistant to HIV infection.

To confer this invulnerability, scientists took the immune cells from HIV-positive patients' own blood, then snipped out a single gene - the first time such a precise alteration has been achieved on a meaningful scale.

When put back in the patient, the cells no longer make a receptor that HIV needs to enter the cell, effectively blocking the virus.

At an AIDS conference Wednesday in Boston, University of Pennsylvania gene-therapy expert Carl June presented data from nine HIV-positive patients who received the novel treatment in Philadelphia, New York, and California. The first patient received the one-shot infusion in July 2009.

The engineered cells remained free of HIV infection in all nine patients and multiplied dramatically in eight of them, accounting for an average of 6 percent of their total supply of the immune cells, known as T cells. The T cells were found in tissue in the patients' guts, an area where HIV builds a reservoir.

No patient suffered serious side effects, although all had temporary symptoms such as headache, chills, or fever.

June, who has worked on other experimental gene therapies for HIV, said the new approach "shows the most promise of any yet tested."

"It's a big accomplishment because this is the first successful attempt at genetic editing," he said. "It gives us an essential tool."

That tool - called "zinc fingers" because an atom of zinc binds to two loops of proteins - was developed by Sangamo BioSciences of Richmond, Calif., the small biotech company that is funding human testing of the engineered T cells.

Zinc fingers are able to recognize specific sequences of DNA. By attaching a protein that cuts DNA, scientists can use zinc fingers like molecular scissors, cutting and then deleting - or inserting - genes. Until now, gene therapy has been imprecise, relying on viruses to insert genes somewhat randomly into a cell's DNA.

"This is elegant work, scientifically very sound, and an important 'proof of concept,' " said Anthony Fauci, an AIDS research pioneer at the National Institutes of Health. It funded the lab research that laid the groundwork for the human studies.

Although producing the HIV-resistant T cells was a technological tour de force - hundreds of exacting steps were involved - the cells conveyed only partial immunity to patients, because there are many kinds of immune cells other than T cells.

The question now, experts said, is whether it is possible to confer total immunity - in effect, cure HIV - by altering the whole immune system.

That's what happened in a fortuitous fluke in 2009. An HIV-positive man in Germany who developed leukemia received a stem-cell transplant from a donor who happened to be naturally resistant to HIV infection.

The donor, it turned out, had a gene mutation that left his T cells unable to make the receptor that HIV latches onto. The mutation - which June and his colleagues created with zinc fingers - was first identified in the 1980s, but population geneticists have traced its origins to the mid-14th century, when it conferred protection against the bubonic plague virus.

"You can inherit one copy or two copies of the mutation," June said. "About 1 percent of people have two copies and are completely resistant to HIV."

Researchers have already shown they can "cure" HIV by deleting the receptor-making gene from blood stem cells, then transplanting these cells - but only in mice.

That study, published in July, was described at Wednesday's conference by lead researcher Paula M. Cannon, a molecular biologist at the University of Southern California.

Although the mouse model was sufficiently exciting to inspire an accompanying editorial, titled "Can HIV be cured with stem-cell therapy?", experts are not sure the approach would be practical for humans. A stem-cell transplant requires destroying the patient's entire blood immune system with toxic drugs, then infusing the stem cells over several weeks to rebuild the system. That's a potentially lethal regimen, especially for a patient who starts out with a compromised immune system.

Another question involves the source of the stem cells. If the patient used his own stem cells, they would be infected with HIV. And if donated stem cells were used, rejection would be a problem.

"Instead of antiretroviral drugs [to treat HIV], the patient would have to take antirejection drugs - which some would say is even worse," noted Fauci. "That is a big stumbling block."

Nonetheless, Sangamo BioSciences had obtained a $14.5 million grant from California to try to develop such a stem-cell-based therapy, company spokeswoman Elizabeth Wolffe said.

Meanwhile, June and his Penn colleague Pablo Tebas are planning a clinical trial that would give the modified T cells to patients with recent HIV diagnoses who don't yet need antiretroviral drugs.

Tebas is hopeful, but said talk of a cure was premature. "It's a step. I don't want to give too much hype to it," he said. "It's a step in a long process."

For Jay Johnson, 50, the second patient to receive the modified T cells, the prospects are thrilling. His total T-cell count - a key indicator of a healthy immune system - has remained twice as high as it was before the treatment.

"I'm ecstatic," said Johnson, the volunteer coordinator at Action AIDS in Philadelphia. "It's really promising. Maybe someday I can come off drug therapy altogether. That would be a blessing."


Contact staff writer Marie McCullough at 215-854-2720

or mcculom@phillynews.com.

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